Affinage

IQCB1

IQ calmodulin-binding motif-containing protein 1 · UniProt Q15051

Length
598 aa
Mass
68.9 kDa
Annotated
2026-06-10
25 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IQCB1 (NPHP5) is a centriolar, transition-zone and basal-body protein required for ciliogenesis and for the selective delivery of signaling cargo to cilia (PMID:25552655, PMID:23446637). Its central function is exerted through a direct interaction with CEP290, mapped to the CEP290 N-terminal region (aa 696–896), which is required for cilia formation; truncating disease mutations abolish CEP290 binding and centrosomal localization and block ciliogenesis (PMID:18723859, PMID:23446637). NPHP5 carries two BBSome-binding sites and maintains BBSome integrity, with its loss selectively dissociating BBS2 and BBS5 and impairing ciliary trafficking of cargos such as smoothened, VPAC2 and Rab8a, while CEP290 governs BBS8 integrity (PMID:25552655). NPHP5 also acts as a sub-distal appendage and basal foot component of the mother centriole, where it is specifically required for basal foot assembly during ciliogenesis (PMID:31177295). Its abundance and localization are controlled by cell-cycle-dependent ubiquitination: BBS11/TRIM32 adds K63 chains and MARCH7 adds K48 chains, while the deubiquitinase USP9X is recruited to the centrosome by NPHP5 in G0/G1/S to protect it and favor cilia assembly (PMID:28498859). Calmodulin binding prevents NPHP5 self-aggregation, and EPB41L5 modulates its ciliary-base localization and its interaction with CEP290 (PMID:23446637, PMID:32501287). Loss of IQCB1 produces a cell-type-specific defect most severe in photoreceptors, where transition zones are malformed and outer-segment proteins fail to traffic, while some other ciliated tissues are spared (PMID:27328943, PMID:36084637).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2008 High

    Established that NPHP5 acts within the nephrocystin network by physically engaging CEP290, defining a molecular partnership underlying ciliopathy phenotypes.

    Evidence Co-IP with deletion mapping plus morpholino knockdown/rescue in Xenopus and double knockdown in zebrafish

    PMID:18723859

    Open questions at the time
    • Did not resolve where in ciliogenesis the NPHP5–CEP290 complex acts
    • No structural detail of the interaction interface
  2. 2013 High

    Defined NPHP5 as a transition-zone/centriolar protein acting at an early ciliogenesis step and separated its two interactions functionally — CEP290 binding drives cilia formation while calmodulin binding prevents self-aggregation.

    Evidence siRNA depletion, domain mapping, localization, disease-mutation analysis and pharmacological rescue

    PMID:23446637

    Open questions at the time
    • Mechanism by which CEP290 binding promotes ciliogenesis not detailed
    • Role of self-aggregation control in vivo unresolved
  3. 2014 High

    Showed NPHP5 maintains BBSome integrity through two BBSome-binding sites and is required for ciliary cargo delivery, linking it directly to ciliary signaling output.

    Evidence siRNA depletion, Co-IP, binding-site mapping, immunofluorescence of ciliary BBSome subunits and cargos

    PMID:25552655

    Open questions at the time
    • How NPHP5 mechanically stabilizes BBS2/BBS5 within the BBSome unknown
    • Whether cargo selectivity is direct or via BBSome remodeling not resolved
  4. 2016 High

    Demonstrated a cell-type-specific requirement: NPHP5 is essential for photoreceptor outer-segment formation and proper transition-zone architecture but dispensable for ciliogenesis in fibroblasts and kidney.

    Evidence Germline gene-trap Nphp5-knockout mouse with ERG, EM, IHC and kidney histology

    PMID:27328943

    Open questions at the time
    • Molecular basis of tissue specificity unexplained
    • Why transition-zone diameter is reduced not mechanistically defined
  5. 2016 Medium

    Characterized photoreceptor pathology in a large-animal NPHP5-LCA model, showing sensory cilia form but outer segments fail, with rod-expressed transcripts selectively downregulated.

    Evidence Comparative phenotyping, gene expression profiling and confocal microscopy of canine NPHP5-mutant retinas

    PMID:27506978

    Open questions at the time
    • Primarily descriptive, limited pathway-level mechanism
    • Cause of differential rod versus cone vulnerability unresolved
  6. 2017 High

    Revealed that NPHP5 levels and localization are gated through the cell cycle by opposing ubiquitination (TRIM32/BBS11 K63, MARCH7 K48) and USP9X-mediated deubiquitination, coupling ciliogenesis to cell-cycle state.

    Evidence Co-IP, linkage-specific ubiquitination assays, cell-cycle synchronization and siRNA depletion

    PMID:28498859

    Open questions at the time
    • Signals controlling USP9X centrosomal dissociation in G2/M unknown
    • Whether ubiquitination directly modulates CEP290/BBSome binding not tested
  7. 2018 Low

    Reported a physical interaction between CNNM4 and IQCB1 modulated by CNNM4 truncation and associated with apoptosis.

    Evidence Co-IP and apoptosis assay with a truncated CNNM4 construct

    PMID:29322253

    Open questions at the time
    • Single Co-IP without reciprocal or functional dissection of how the interaction affects IQCB1
    • No link to ciliary function established
  8. 2019 High

    Placed NPHP5 in the sub-distal appendage/basal foot of the mother centriole, identifying it as specifically required for basal foot assembly during ciliogenesis.

    Evidence siRNA depletion, co-localization, epistasis by sequential depletion of BF/SDA components and rescue

    PMID:31177295

    Open questions at the time
    • How basal foot assembly couples to ciliogenesis mechanistically unclear
    • Direct partners within the BF hierarchy not all identified
  9. 2020 Medium

    Identified EPB41L5 as a regulator of IQCB1 ciliary-base localization and of its CEP290 interaction, adding an upstream modulator of the NPHP5–CEP290 axis.

    Evidence Co-IP, overexpression/knockdown localization in mammalian cells, and zebrafish genetic synergy with left-right patterning readout

    PMID:32501287

    Open questions at the time
    • Mechanism by which EPB41L5 displaces IQCB1 not defined
    • Single-lab finding without reciprocal structural validation
  10. 2022 Medium

    Showed in patient-derived iPSC retinal models that IQCB1 mutations cause CEP290 destabilization, axoneme/outer-segment defects and visual-pigment mislocalization, all rescuable by AAV gene augmentation.

    Evidence Patient iPSC-derived RPE and retinal organoids with immunofluorescence, CEP290 Western blot and AAV rescue

    PMID:36084637

    Open questions at the time
    • Whether CEP290 loss is cause or consequence of the gating defect not fully resolved
    • Single-lab human model system

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NPHP5 integrates its multiple roles — CEP290 binding, BBSome cargo gating, basal foot assembly, and ubiquitin-regulated turnover — into a single coordinated ciliogenesis program, and what underlies its tissue-specific essentiality, remains unresolved.
  • No integrated structural model of the NPHP5–CEP290–BBSome assembly
  • Molecular basis of photoreceptor-selective requirement unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005815 microtubule organizing center 3 GO:0005929 cilium 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9609507 Protein localization 1
Partners
CALM1CEP290CNNM4EPB41L5MARCH7TRIM32USP9X
Complex memberships
BBSomebasal footsub-distal appendage

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 NPHP5 contains two separate BBSome-binding sites and interacts with the BBSome to mediate its integrity; depletion of NPHP5 specifically causes dissociation of BBS2 and BBS5 from the BBSome and loss of their ciliary trafficking without compromising other subunits. CEP290, which directly binds NPHP5, additionally controls BBS8 integrity within the BBSome. Loss of NPHP5 or CEP290 selectively impairs delivery of BBSome cargos (smoothened, VPAC2, Rab8a) to cilia. siRNA depletion, co-immunoprecipitation, mapping of binding sites, immunofluorescence of ciliary BBSome subunits and cargos Human molecular genetics High 25552655
2008 Nephrocystin-5 (NPHP5) physically interacts with the N-terminal domain of nephrocystin-6 (NPHP6/CEP290); the interacting region was mapped to amino acids 696–896 of NPHP6. Knockdown of NPHP5 in Xenopus caused neural tube closure defects that were phenocopied by expression of the nephrocystin-5-binding fragment of NPHP6 and rescued by co-expression of NPHP5, confirming functional in vivo interaction. Combined knockdown of zNPHP5 and zNPHP6 in zebrafish produced synergistic phenotypes. Co-immunoprecipitation with deletion mapping, Xenopus morpholino knockdown and rescue, zebrafish double knockdown Human molecular genetics High 18723859
2013 NPHP5 is a centriolar/transition zone protein whose depletion inhibits an early step of ciliogenesis. NPHP5 interacts with both CEP290 and calmodulin (CaM): CEP290 binding is required for ciliogenesis, while CaM binding prevents NPHP5 self-aggregation. Disease-causing truncating mutations abolish CEP290 binding and centrosomal localization, compromising cilia formation. A modifier mutation disrupts CaM binding without affecting ciliogenesis. siRNA depletion, co-immunoprecipitation, domain mapping, immunofluorescence/localization, disease-mutation functional analysis, pharmacological rescue Human molecular genetics High 23446637
2017 NPHP5 undergoes cell-cycle-dependent K63 ubiquitination by the E3 ligase BBS11/TRIM32, and K48/K63 ubiquitination by MARCH7/axotrophin. The deubiquitinase USP9X directly binds NPHP5 and is recruited to the centrosome by NPHP5 during G0/G1/S phase to protect NPHP5 from ubiquitination and favour cilia assembly. In G2/M, USP9X dissociates from the centrosome, allowing BBS11-mediated K63 ubiquitination of NPHP5, triggering its delocalization and cilia loss. USP9X depletion also allows centrosomal accumulation of MARCH7, which K48 ubiquitinates NPHP5 to trigger its proteasomal degradation. Co-immunoprecipitation, ubiquitination assays distinguishing K48/K63 linkages, siRNA depletion, cell-cycle synchronization, immunofluorescence PLoS genetics High 28498859
2016 In Nphp5-knockout mice, basal bodies form but transition zones are aberrant (reduced diameter), and outer segment transmembrane proteins accumulate in the ER by postnatal day 6. NPHP5 is essential for photoreceptor outer segment formation but is dispensable for ciliogenesis in mouse embryonic fibroblasts and kidney function, indicating a cell-type-specific requirement. Germline Nphp5-knockout mouse (gene-trap), electroretinography, immunofluorescence with EGFP-CETN2, electron microscopy of transition zones, ER accumulation assay, kidney histology FASEB journal High 27328943
2019 NPHP5 is a novel sub-distal appendage (SDA) and basal foot (BF) component of the mother centriole/basal body. NPHP5 is specifically required for basal foot (BF) assembly during ciliogenesis but is dispensable for SDA assembly. NPHP5 cooperates with a subset of SDA/BF proteins in a defined hierarchical order to organize BF; loss of NPHP5 simultaneously inhibits BF assembly and primary ciliogenesis, phenotypes rescuable by manipulating BF assembly pathway components. siRNA depletion, immunofluorescence co-localization, epistasis by sequential depletion of BF/SDA components, rescue experiments Cellular and molecular life sciences High 31177295
2022 Patient-derived iPSC-differentiated RPE and retinal organoids carrying NPHP5 mutations show aberrantly elongated ciliary axonemes, impaired photoreceptor outer segment development, and mislocalization of visual pigments to the cell soma. All patient-derived cells show reduced levels of CEP290 protein, suggesting NPHP5 loss impairs ciliary gating and cargo transport through destabilization of CEP290. AAV-mediated IQCB1 gene augmentation rescues these phenotypes. iPSC reprogramming, differentiation to RPE and retinal organoids, immunofluorescence, Western blot for CEP290 levels, AAV rescue Stem cell reports Medium 36084637
2020 EPB41L5 forms a complex with IQCB1/NPHP5 and regulates its localization at the ciliary base. Overexpression of EPB41L5 reduces IQCB1 localization at the ciliary base, while EPB41L5 knockdown increases it. EPB41L5 also decreases IQCB1 interaction with CEP290. Genetic synergy between epb41l5 and iqcb1 was observed in zebrafish, and epb41l5-deficient embryos showed reduced cilia motility and left-right patterning defects. Co-immunoprecipitation, overexpression and knockdown immunofluorescence in mammalian cells, zebrafish genetic interaction/synergy, left-right patterning assay Journal of cell science Medium 32501287
2018 CNNM4 physically interacts with IQCB1; a truncated CNNM4 protein starting at R605 significantly increases the interaction with IQCB1 and the rate of apoptosis. Co-immunoprecipitation, apoptosis assay with truncated CNNM4 construct Molecular genetics and genomics Low 29322253
2016 In the canine NPHP5-LCA model, rod and cone photoreceptors form a sensory cilium but develop and function abnormally; L/M cones are more severely affected than S-cones. Absence of outer segments in mutant cones indicates ciliary dysfunction. Genes expressed in rod (or both rod and cone) photoreceptors are significantly downregulated in mutants, while cone-only expressed genes are unchanged. Comparative phenotyping of canine NPHP5-mutant retinas, gene expression profiling, confocal microscopy Human molecular genetics Medium 27506978

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Human molecular genetics 102 21245082
2011 IQCB1 mutations in patients with leber congenital amaurosis. Investigative ophthalmology & visual science 96 20881296
2014 Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery. Human molecular genetics 75 25552655
2008 Genetic and physical interaction between the NPHP5 and NPHP6 gene products. Human molecular genetics 67 18723859
2013 Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis. Human molecular genetics 60 23446637
2011 Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome. Archives of ophthalmology (Chicago, Ill. : 1960) 55 21220633
2011 Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. Human mutation 53 21901789
2016 Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation. Human molecular genetics 40 27506978
2013 IQCB1 and PDE6B mutations cause similar early onset retinal degenerations in two closely related terrier dog breeds. Investigative ophthalmology & visual science 39 24045995
2017 USP9X counteracts differential ubiquitination of NPHP5 by MARCH7 and BBS11 to regulate ciliogenesis. PLoS genetics 35 28498859
2016 Ciliopathy-associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 27328943
2021 Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosis. Molecular therapy : the journal of the American Society of Gene Therapy 29 33781914
2022 In vitro modeling and rescue of ciliopathy associated with IQCB1/NPHP5 mutations using patient-derived cells. Stem cell reports 27 36084637
2017 Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes). Scientific reports 20 28322220
2018 Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1. Molecular genetics and genomics : MGG 15 29322253
2020 Transient pupillary light reflex in CEP290- or NPHP5-associated Leber congenital amaurosis: Latency as a potential outcome measure of cone function. Vision research 13 32088401
2018 Rescue of cone function in cone-only Nphp5 knockout mouse model with Leber congenital amaurosis phenotype. Molecular vision 13 30713422
2019 Requirement of NPHP5 in the hierarchical assembly of basal feet associated with basal bodies of primary cilia. Cellular and molecular life sciences : CMLS 8 31177295
2013 Clinical features and mutation of NPHP5 in two Chinese siblings with Senior-Løken syndrome. Nephrology (Carlton, Vic.) 8 24674142
2011 Senior-Loken syndrome secondary to NPHP5/IQCB1 mutation in an Iranian family. NDT plus 5 25984213
2024 IQCB1 (NPHP5)-Retinopathy: Clinical and Genetic Characterization and Natural History. American journal of ophthalmology 4 38522724
2020 Epb41l5 interacts with Iqcb1 and regulates ciliary function in zebrafish embryos. Journal of cell science 3 32501287
2025 Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome. NPJ genomic medicine 1 40263280
2025 A Novel NPHP5 Gene Mutation in Three Siblings With Nephronophthisis Without Retinitis Pigmentosa: A Case Report. Case reports in genetics 0 40331022
2025 Senior-Løken syndrome with IQCB1/NPHP5 mutation in an adult: a case report. Journal of medical case reports 0 41316455

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